The mechanisms of type 2 diabetes (T2DM) remission after gastric bypass surgery (GBP) are unclear. The levels of the gut hormones incretins and their effect on insulin secretion, which is impaired in T2DM, markedly increase after GBP. The anatomical changes of GBP, rather than weight loss, seem to be responsible for the changes of incretins. The objective of this proposal is to investigate the different mechanisms by which GBP and gastric banding (GB) affect glucose control. We wish to understand the role of weight loss versus changes in gut peptides in the short and long term morbidity in patients with T2DM randomized to GBP or GB. AIM 1 will compare the short term effect of GBP and GB on incretin levels and effect after an equivalent 10 kg weight loss, testing the hypothesis that incretin levels and effect will increase more after GBP than after GB. AIM 2 will study the long-term changes in the incretin levels and effect after oral glucose and during a 24-h multiple meal diet, before and 2 years after GBP and GB, testing the hypothesis that mean incretin levels is greater after GBP than after GB. AIM 3 will study the changes of insulin secretion in response to IV glucose (AIRg) and insulin sensitivity (Si), measured by the minimal model, 2 years after GBP and GB, testing the hypothesis that for an equivalent increase of Si, AIRg will increase more after GBP than after GB. PUBLIC HEALTH RELEVANCE: The increased prevalence of obesity and type 2 diabetes has resulted in a surge in the number of patients seeking surgical weight loss. Gastric bypass surgery (GBP) results in 50-70% excess body weight loss with resolution of type 2 diabetes (T2DM) in 84% of cases. The mechanisms by which diabetes improves after GBP are unclear. Glycemic control occurs long before significant weight loss, suggesting that the nature of the procedure, rather than the weight loss, is responsible for the T2DM improvement. Recent data have singled out the role of the gut hormones known as incretins in diabetes improvement after GBP, but not after another type of surgery, gastric banding (GB). We propose to study, in patients with morbid obesity and T2DM, randomized to GBP or GB, the effect of the surgery in the short and the long term on incretins levels and effect, insulin secretion in response to IV glucose and diabetes control. We wish to apply our findings to possible medical alternatives for the treatment of obesity and T2DM.